The present invention relates to orally administered suspensions of pharmaceutically active substances of the NSAID type (nonsteroidal-antiinflammatory drugs), but particularly the antirheumatic agent meloxicam and a process for preparing them.
Various pharmaceutical forms are used for oral administration of drugs. Thus, in addition to solid single-dose forms such as tablets, hard and soft gelatin capsules, liquid forms such as solutions and syrups are also given, in which the dose to be administered can be adjusted by means of the volume given.
Solutions and syrups have the advantage that they can be taken easily and safely even by patients who have trouble taking solid, single-dose forms (e.g. children and older patients). Liquid preparations are advantageously easy to measure out for veterinary use.
However, it should be borne in mind that even with the same dosage and the same method of administration, the activity of the same pharmaceutical substance may vary. These variations mean that the therapeutic effect clinically demonstrated for a drug in a specific preparation cannot be achieved with a different preparation of the same drug, and furthermore within a course of treatment one preparation cannot readily be exchanged for another. Preparations which are not therapeutically equivalent are known as xe2x80x9cnon-bioequivalentxe2x80x9d. For the oral administration of pharmaceutical preparations, the drug is usually absorbed faster from liquid preparations, particularly solutions, than from tablets or capsules and these drugs are consequently not always bioequivalent (Bauer K. H.;
Frxc3x6mming K.-H.; Fxc3xcihrer C., Pharmazeutische Technologie, 5th Edition 1997, Gustav Fischer Verlag, Stuttgart, page 213).
Meloxicam is an antirheumatic agent belonging to the NSAID""s. NSAID""s are cyclooxygenase inhibitors, whilst meloxicam has been shown to have a selective inhibitory effect on the isoenzyme COX-2 and consequently a reduced risk of undesirable gastrointestinal side effects. For safe administration of meloxicam and other active substances, e.g. other NSAID""s, a liquid oral preparation is desirable as an alternative to the solid form (capsule, tablet), particularly in pediatrics and in veterinary use.
The complex objective of the present invention was primarily to produce an orally administered liquid preparation of meloxicam. The formulation should take effect rapidly when first used in acute cases. However, the substance is preferably used for long-term therapy. In such long-term therapy, the liquid oral formulation should be bioequivalent to other oral formulations (tablet, capsule) in the steady state in order to allow therapy with either a liquid or solid oral formulation as desired. At the same time, the liquid preparation should have a pleasant flavor in order to be acceptable to children and thus ensure that it is taken as specified and the treatment is ensured. In addition, the liquid preparation should preferably not contain any ethanol, since the possibility of ethanol having a harmful effect even in physiologically acceptable, non-toxic concentrations cannot be ruled out completely, particularly in children. Moreover, when ethanol is used, there is the risk of abuse by alcohol-dependent patients or relapse on the part of formerly alcohol-dependent patients. The suitability of the formulation for diabetic patients should also be taken into account. To ensure exact dosage of a liquid oral preparation of meloxicam, the preparation should also be homogeneous over a sufficient length of time during its removal from the primary packaging.
In addition, the preparation should also be suitable for use in animals. The veterinary formulation should also have a smell and flavor which are suitable for numerous types of animals which can be treated with antirheumatic drugs, particularly various species of mammals, to ensure that the course of treatment is completed and the therapy is guaranteed, on the basis of good acceptance.
One obvious way of preparing a liquid oral formulation of a pharmaceutically active substance is to dissolve the substance in physiologically inert solvents (especially pharmaceutical grade water). However, this approach is unsuitable in many cases. To ensure the desired pleasant taste of a liquid oral formulation, e.g. meloxicam, it is not possible to use solutions, since the substance in the dissolved state has an unpleasant taste of its own. This taste is apparent in all the solvents which can be used for the oral administration of solutions and cannot be adequately masked even by the addition of flavor correcting agents such as flavorings and sweeteners.
However, meloxicam does not have a noticeable flavor of its own when the substance is suspended in a physiologically inert dispersion medium for a liquid oral preparation and the solubility of meloxicam in the dispersion medium used is very slight. This provided a suitable approach to solving the problem. This approach can be applied analogously to other active substances of the NSAID category. Since a clearly noticeable unpleasant taste is present even at a concentration of over 500 xcexcg/ml of dissolved meloxicam, the solubility of this active substance in the dispersion media used must be below this threshold.
When a suspension of active substance is used there is the problem that the homogeneity of the suspension has to be ensured for a sufficient length of time during removal from the primary packaging (e.g. glass bottle, 100 ml) to ensure accurate dosing. However, the sedimentation of solids dispersed in liquid media cannot be prevented but only delayed for a greater or lesser period. One conventional approach to delaying sedimentation is, for example, by increasing the viscosity of the dispersing medium by the addition of suitable substances, e.g. organic hydrocolloid forming agents, e.g. cellulose ether, or silicon dioxide as a thickener. Increasing the viscosity of the dispersing agent does, however, have the serious disadvantage that it makes it considerably more difficult to redisperse the sediment formed, to the extent that if the suspension is too viscous it is impossible to reconstitute the suspension at all. Moreover, the caking caused by contact of the individual particles under the effects of gravity during storage of the suspension must be avoided. It is known from the literature to prevent caking by, for example, controlled flocculation of such systems by the adsorption of potential-determining ions (Sucker H., Fuchs P., Speiser P., Pharmazeutische Technologie, 5th Edition 1991, Georg Thieme Verlag, Stuttgart, p. 423). The industrial manufacture of stable suspensions by controlled flocculation is subject to limitations, since it is difficult to reproduce the optimum properties of suspension systems of this kind owing to the variability of the suspended solid and the stability of the suspension is considerably affected by the adjuvants used.
Surprisingly, the suspension of a pharmaceutically active substance of the NSAID type can be stabilised by the addition of small amounts of highly dispersed silicon dioxide in the presence of small amounts of hydrophilic polymers. Because of the low concentration of highly dispersed silicon dioxide and hydrophilic polymer in the dispersion medium, the viscosity is low; unwanted increased in viscosity, which will prevent reconstitution of the suspension, caused by gel-like thickening of the dispersion medium does not occur if at the same time small amounts of hydrophilic polymer which are soluble in the dispersion medium are added to the medium and the silicon dioxide is added to the suspension with the aid of high shear forces. Suitably high shear forces can be produced with a suitable shear-intensive homogenising mixer, e.g., with mixers of the series xe2x80x9cBecomixxe2x80x9d made by Messrs. A. Berents GmbH and Co. KG, Henleinstr. 19, D-28816 Stuhr, which comprise rapidly rotating homogenizers working on the rotor-stator principle. A circumferential rotor speed of about 25 to 27 m/s is particularly suitable for generating sufficiently high shear forces and is used to introduce the highly dispersed silicon dioxide into the dispersing agent for about 10-15 minutes, e.g., using the mixers Becomix RW 15/RW 60/RW 1000. This produces a special siloid structure which consists of a spongy three-dimensional structure of hydratised highly dispersed silicon dioxide shot through with cavities, the active substance being adsorbed onto said structure.
Suitable highly dispersed silicon dioxide has a specific surface area of at least 50 m2/g, preferably 100 to 400 m2/g, for example, whilst a specific surface area of about 200 m2/g is particularly preferred (e.g. Aerosil(copyright) 200).